PROJECT 1- SUMMARY/ABSTRACT There is a large degree of heterogeneity in the age of onset, neuropathology and rate of disease progression in patients with Alzheimer's disease (AD). Why some patients are particularly vulnerable to the development of AD is still not yet understood. We recently showed that people with rapidly progressive Alzheimer's disease (rpAD) had a significantly different amyloid plaque proteome from those with typical sporadic AD. These plaque protein differences between AD subtypes offered insight into factors that contribute to plaque development and factors that may influence the rate of progression of AD. We have since generated preliminary data that suggests that similar plaque proteomic differences are also present in another subgroup of AD patients vulnerable to AD; apoE4 carriers. The comparison of the plaque proteome in apoE4 and apoE3 carriers identified similar protein differences in plaque proteins that were most altered in rpAD, as well as similarly decreased levels of plaque-associated astrocyte proteins in apoE4 carriers. In this project we will test the hypothesis that apoE4 carriers will have a significantly altered proteome of amyloid plaques and cerebral amyloid angiopathy (CAA) in comparison to apoE3 and apoE2 carriers. We expect that proteomic differences in apoE4 carriers will be similar to those observed in rpAD. This study will identify protein differences present in plaques and CAA in individuals particularly vulnerable to AD; specifically comparing the protein differences that result from apoE4, apoE3 and apoE2 expression. Importantly, we will determine the proteome composition of apoE2, 3 and 4 carriers for the full spectrum of AD from preclinical normal, mild cognitive impairment and late stage AD. This data will be used as a comparative human dataset for rodent proteomic studies proposed in projects 1 and 2. We will identify and validate protein differences that are of particular interest, which represent potential novel therapeutic targets and biomarkers of AD. The specific aims are: 1) Characterize the differences in the plaque proteome between apoE4, apoE3 and apoE2 carriers in preclinical cognitivenormal, MCI and late AD cases. 2) Characterize the differences in the cerebral amyloid angiopathy proteome between apoE4, apoE3 and apoE2 carriers in preclinical cognitive normal, M CI and late AD case s. 3) To validate the accumulation of novel amyloid associated proteins in AD neuropathological lesions and to determine the role of these proteins in driving AD pathology development.